Skin wounds disrupt the continuity of the protective tissue interface between the inner organs of the human body and the external environment. Causes of skin wounds include burns, resulting from exposure to thermal extremes, radiation (UV or ionizing) or chemicals; mechanical injury, and pathologic conditions associated with necrotic complications, in particular diabetes, high blood pressure and vascular diseases.
Wound bed preparation (WBP) refers to a medical intervention activity aimed at any or all of: cleaning the wound bed of any foreign material and/or dead tissue (such as eschar in the case of burned skin); increasing the amount of granulation tissue in chronic and recalcitrant wounds; reducing the number of abnormal or senescent cells within the wound or at the wound edge; decreasing exudates and edema; and decreasing bacterial burden, so as to initiate and promote the wound healing process. The technology selected for WBP depends on the wound etiology and in turn, influences the nature and subsequent behavior of the wound bed. Debridement is usually an essential component of wound bed preparation.
Surgical debridement involves excision of clinically diagnosed dead tissues, and is terminated at a point when the surgeon judges that the wound bed is clean, usually on the basis of the bleeding pattern. This method is traumatic and non-selectively sacrifices large amounts of uninjured tissue, but is quick and effective. The surgically debrided wound bed is characterized by a raw surface with sharply transected cutaneous components, mainly dermal collagen matrix, skin appendages (hair roots, sweat and sebaceous glands) and blood vessels. The transected dermal matrix is bleeding, flat and smooth. If sufficient dermis remains with epithelial components from the appendages, this bed may heal by epithelialization upon provision of proper conditions. Near or full thickness defects may be repaired by autografting under stabilizing and protective dressing. This scenario is typical for acute and burn wounds.
Conventional (or “conservative”) non-surgical debridement involves application of chemical and/or other topical preparations, soakings and repeated dressings over a long period of time i.e. up to several weeks. Accordingly, this technique is considerably slower and less efficient than surgical debridement. The resultant wound bed is usually a mixture of exposed tissues, granulating tissue, fibrinous deposits with possible residues of eschar, pus and bacterial aggregates. Healing may require additional surgery and autografting. This condition typifies chronic, recalcitrant and slow healing acute wounds.
A more recent debridement technique, in particular for burn wounds, is rapid enzymatic debridement using mixtures of proteolytic enzymes. Particularly effective are proteolytic enzymes extracted from the stem of the pineapple plant, as disclosed by the inventor of the present invention, for example in WO 98/053850 and WO 2006/0006167, and as provided in the product marketed under the trade name Debrase®.
This technique is reported to selectively remove dead tissue within four hours of application, and leave healthy tissue substantially intact. Accordingly, rapid enzymatic debridement may also be referred to as “selective enzymatic debridement” when only dead tissue is eliminated. The resultant wound bed is characterized by a raw surface dermal matrix that has a “furred” appearance, in contrast to surgically debrided and sharply transected tissue. Blood vessels and skin appendages in the wound bed may be partially occluded, and significant portions of dermis are preserved with epithelial components from the appendages. This type of wound bed may heal by epithelialization upon provision of proper conditions. Near or full thickness defects may be repaired by autografting under stabilizing and protective dressing.
The raw surface remaining after rapid enzymatic debridement comprises the upper layer of remaining healthy tissue, and may be defined as the “interface layer”. All viable components in the interface layer, such as epithelial elements and dermal remnants, form the basis for spontaneous epithelialization and healing. The interface layer has biological and physiological characteristics which differ from that of the surgically or conventional non-surgically debrided beds. For example, the surgically debrided bed consists of transected tissue and its structures and requires protection, mainly against desiccation. The conventional non-surgically debrided bed contains smaller or larger quantities of granulation tissue, which requires different care than the raw surface, particularly upon formation of bacterial biofilm. The interface layer resulting from selective enzymatic debridement needs a specific, dynamic dressing that should comply to its changing needs in order to promote the healing process. The prior art does not provide any such means for providing a dynamic and adjustable microenvironment in the interface layer.
The prior art discloses various synthetic polymer-biopolymer composite materials, including coverings and dressings for burns and other wounds. Many such materials include open cell polymeric foams i.e. foams characterized by interconnecting pores or conduits which open to the outer surfaces. Such foams often form a part of a multi-layered structure; in some cases a separate layer is formed from a biopolymer such as hyaluronic acid. Other disclosures relate to co-polymers, cross-linked forms and covalently linked combinations of polyurethanes and hyaluronic acid.
U.S. Pat. No. 7,112,417 discloses a composite for tissue engineering and other tissue applications, comprising a biocompatible filamentous first layer and a biocompatible foam second layer, wherein the foam preferably has a gradient structure, is bioabsorbable and is inter alia an aliphatic polyester. According to the disclosure, the interconnecting pores of the foam are in the size range from about 10 μm to about 200 μm or greater, and may be co-lyophilized, coated or filled with pharmaceutically active compounds or biopolymers inter alia hyaluronic acid.
U.S. Pat. No. 6,552,244 discloses a multi-layered wound dressing which comprises: (a) an absorbent layer inter alia a fibrous layer comprising gel-forming fibres inter alia hyaluronic acid, having a water absorbency of at least 10 μg with a low lateral wicking rate; (b) a transmission layer inter alia a polyurethane foam, having a high moisture vapor transmission rate overlying the side of said absorbent layer furthest from the wound during use; and, (c) a spreading layer having high lateral wicking rate disposed between the absorbent and transmission layer.
U.S. Pat. No. 6,855,860 discloses a non-occlusive composite wound dressing comprising a natural polymer wound-healing layer comprising isolated polymer fibers, and a synthetic polymer foam layer having at least one pore-containing surface contacting said natural layer and physically adhered to said natural layer. According to the disclosure, the synthetic polymer may be an open-pore polyurethane foam, the natural polymer may be a polysaccharide, and the natural polymer layer may incorporate a wound healing agent inter alia glycosaminoglycans.
U.S. Pat. No. 7,041,868 discloses a wound dressing comprising a first layer located adjacent to the wound comprising a fibrous non-woven bioabsorbable material, having pores in the size range 50-400 microns, adapted for serving as a scaffold for cell attachment and proliferation; and a second layer which is in contact with the first layer comprising an absorbent gel forming material and adapted for serving as a barrier to cell adhesion and penetration. According to the disclosure, the first layer can be formed from inter alia cross-linked hyaluronic acid, or can include hyaluronic acid as a fiber coating, or it can be a foam, and the second layer may be inter alia a foam or hydrogel or any structure having pore size less than about 10 microns in the hydrated state.
U.S. Pat. No. 6,596,293 discloses a polymeric delivery device for controlled release of a bioactive agent, the device formed by treating a biopolymer with a cross-linking agent whereby the cross-linking agent is simultaneously polymerized and formed into cross-linking moieties with the biopolymers, According to the disclosure, the preferred cross-linking agents are polyisocyanate-terminated polyurethane or polyurethane urea pre-polymers, which upon use of water as solvent results in a foam material. It is further disclosed that suitable biopolymers include glycosaminoglycan from animal tissue.
U.S. Pat. No. 6,656,974 discloses a foam material for wound dressings, comprising a solid cross-linked form of an anionic polymer, which is preferably an alignate, and may further comprise hyaluronic acid. According to the disclosure, the foam may incorporate inter alia a hydrophilic polymer or a wound healing agent.
U.S. Pat. No. 5,644,049 discloses a biomaterial comprising a non-chemically crosslinked interpenetrating polymer network comprising a first component selected from a hyaluronic acid ester and a hyaluronic acid salt, and a second component which is a synthetic chemical polymer. This patent discloses inter alia formation of transparent homogeneous films by amalgamation of various hyaluronic acid derivatives and polyurethanes.
U.S. Patent Application Publication No. 2007/0185426 discloses a delivery system for applying reduced pressure tissue treatment to a tissue site inter alia a burn wound, comprising a multi-layer apparatus having a tissue contact layer which includes a scaffold; a release layer and a manifold layer. According to the disclosure, the invention is a biocompatible wound dressing which includes a foam pad, preferably comprising highly reticulated open-cell polyurethane foam, and the tissue contact layer may include inter alia hyaluronic acid. The pore size of the scaffold may be between 50 and 500 microns.
PCT publication No. WO 2005/052043 discloses a flexible polyurethane foam for cosmetic puffs containing 0.001 to 2% by mass hyaluronic acid, which is formed by a process comprising mixing organic polyisocyanate, polyol, catalyst, foam stabilizer, aqueous hyaluronic acid solution and an inert gas, followed by foaming and curing.
PCT publication No. WO 2004/039421 discloses a polyurethane foam dressing for a wound filler, which includes a hydrophilic foam containing a plurality of open cells with a diameter of 50 to 400 microns and a plurality of pores with a diameter of 10 to 80 microns. According to the disclosure, the foam is produced by mixing and agitating 40 to 75 wt % pre-polymer, 15 to 45 wt % foaming agent, 5 to 35 wt % crosslinking agent, 0.5 to 15 wt % additive containing a surfactant, a moisturizing agent, and a pigment, injecting the resulting mixture into a mold, and foaming the mixture while it is injected into the mold. Further disclosed is that the additive and/or the moisturizing agent may be inter alia hyaluronic acid.
Cho et al discloses preparation and relative efficacy of polyurethane foam wound dressings including various additives inter alia hyaluronic acid, alone or hyaluronic acid in combination with silver sulfadiazine. According to the disclosure, impregnated polyurethane foams are formed by incorporating the additives into the polyurethane foaming reaction and have open cells of 50 to 200 microns and density of 0.234 to 0.26 g/cm3 (Cho et al (2002) J Mater Sci Mater Med. 13(9):861-5).
Davidson et al disclose use of hyaluronic acid and hyaluronic acid ethyl ester formulations in a sodium alginate vehicle under an occlusive, polyurethane dressing for wound healing in experimental animal systems (Davidson et al (1991) Clin Mater 8(1-2):171-7).
Wound dressings incorporating hydrophilic, water-absorptive polyurethane materials are disclosed for example, in U.S. Pat. Nos. 6,803,495; 5,844,013; 5,782,787; 4,733,659; 4,655,210; 4,550,126; 4,233,969; 3,978,266; 3,927,669, and 3,648,692 and in Patent Application Publication No. 2007/0254974.
Numerous wound dressings are commercially available, including for example, foam-based products such as PolyMem™ and Biatain™; hyaluronan-based products such as Hyalomatrix™, Jaloskin™ and collagen-based products such as Fibracol™ and Integra™. None of the prior art products are designed for use in wound beds following rapid enzymatic debridement, nor do the prior art products enable delivery of different pharmaceutical agents according to changing conditions and progressive stages of healing in the interface layer, without removing the dressing layer and disruption of the healing wound.
There remains an unmet need for a wound dressing that facilitates delivery, exchange or withdrawal of different pharmaceutical agents or substances according to changing conditions and progressive stages of healing in an interface layer microenvironment, without removal of the dressing layer and disruption of the healing wound. There is also an unmet need for a wound dressing that is appropriate for use in wound beds following debridement by various means, including rapid enzymatic debridement.